The development of exceptionally potent inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid) and anandamide (an endogenous ligand for cannabinoid and vanilloid receptors), is detailed. With the help of an extensive set of collaborations that will provide not only the in vitro characterization of the inhibitors, but also their in vivo evaluation (animal pain, sleep, anxiety, and multiple sclerosis models) and characterization (PK properties, metabolism), the studies will clarify the role of endogenous oleamide and anandamide, establish the utility of FAAH as a therapeutic target, and potentially provide therapeutic agents for the treatment of sleep disorders, anxiety, epilepsy, pain, cancer, Parkinson's and Huntington's disease, stroke, and/or multiple sclerosis. Preliminary studies conducted over a period spanning 5 years have been extensive, providing the first class of exceptionally potent, competitive inhibitors of FAAH and defining key structural features that impact future inhibitor design. These studies have provided a set of a-ketoheterocycle FAAH inhibitors with Ki's that drop below 200 pM and that are l00-1000 times more potent than the corresponding trifluoromethyl ketones.